title: Peroxisome proliferator-activated receptor-α agonists protect cortical neurons from inflammatory mediators and improve peroxisomal function.
abstract: Inflammation is known to cause significant neuronal damage and axonal injury in many neurological disorders. Among the range of inflammatory mediators, nitric oxide is a potent neurotoxic agent. Recent evidence has suggested that cellular peroxisomes may be important in protecting neurons from inflammatory damage. To assess the influence of peroxisomal activation on nitric oxide-mediated neurotoxicity, we investigated the effects of the peroxisomal proliferator-activated receptor (PPAR)-α agonist fenofibrate on cortical neurons exposed to a nitric oxide donor or co-cultured with activated microglia. Fenofibrate protected neurons and axons against both nitric oxide donor-induced and microglia-derived nitric oxide-induced toxicity. Moreover, cortical neurons treated with this compound showed a significant increase in gene expression of ABCD3 (the gene encoding for peroxisomal membrane protein-70), with a concomitant increase in protein levels of PPAR-α and catalase, which was associated with a functional increase in the activity of this enzyme. Collectively, these observations provide evidence that modulation of PPAR-α activity and peroxisomal function by fenofibrate attenuates nitric oxide-mediated neuronal and axonal damage, suggesting a new therapeutic approach to protect against neurodegenerative changes associated with neuroinflammation.
authors.affiliation: University of Bristol Institute of Clinical Neurosciences, Frenchay Hospital, Bristol BS16 1JB, UK. elizabeth.gray@bristol.ac.uk
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gray
authors.forename: Mark
authors.initials: M
authors.lastname: Ginty
authors.forename: Kevin
authors.initials: K
authors.lastname: Kemp
authors.forename: Neil
authors.initials: N
authors.lastname: Scolding
authors.forename: Alastair
authors.initials: A
authors.lastname: Wilkins
mesh_terms: D000818:Animals; D002374:Catalase / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D018920:Coculture Techniques; D011345:Fenofibrate / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism / Q000633:toxicity; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D047493:PPAR alpha / Q000819:agonists*; D020675:Peroxisomes / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000960:Hypolipidemic Agents; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D047493:PPAR alpha; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D009569:Nitric Oxide; D007371:Interferon-gamma; D002374:Catalase; D011345:Fenofibrate